Human T cell leukemia virus type 1 (HTLV-1) was the first discovered pathogenic human retrovirus. HTLV-1, the etiologic agent of adult T cell leukemia (ATL), encodes a viral oncoprotein, Tax that is necessary and sufficient for viral transformation. HTLV-1 is the prototypic member of a human retrovirus family that also includes HTLV-2, which has not been definitively linked to any human disease. HTLV-1 and -2 are closely related to the simian T cell leukemia viruses, STLV-1 and -2, respectively. In 2005, the human homologue (HTLV-3) of a third simian retrovirus group, STLV-3, was independently isolated twice from Central African primate hunters, and a third independent isolation of HTLV-3 from humans was recently reported. The genome of the HTLV-3 (2026ND) isolate, in particular the Tax gene, is more closely related to HTLV-1 than to HTLV-2, especially in domains that are thought to be important for transformation. The broad distribution of STLV-3 in African primates and independent isolation of HTLV-3 multiple times from humans, suggest that HTLV-3 is prevalent in Africa. An additional human retrovirus, HTLV-4, was also isolated from an African primate hunter in 2005 and is distinct from all known HTLVs and STLVs. In contrast to HTLV-3, the HTLV-4 genome, in particular the Tax gene, is more closely related to HTLV-2 than to HTLV-1. This application is based on the hypothesis that the HTLV-3 Tax protein possesses oncogenic properties while the HTLV- 4 Tax protein does not. This hypothesis will be investigated in two specific aims that focus on determining the transforming potential, transcriptional activity, and protein interacting partners of the HTLV-3 and HTLV-4 Tax proteins. Since HTLV-3 and HTLV-4 appear to be emerging as new human retroviruses, it is critical that we determine the potential of these viruses to cause disease in humans. PUBLIC HEALTH RELEVANCE: Viruses are important causes of cancer in animals and in humans. One particular virus called HTLV-1 is known to cause a type of leukemia in humans. Two new viruses were recently found in humans and these new viruses are very closely related to HTLV-1. Therefore, we think that at least one of the new viruses may cause cancer in humans. HTLV-1 makes a protein called Tax that is necessary for the virus to cause cancer. We plan to compare the Tax protein made by HTLV-1, with the Tax protein made by each of the two new viruses so that we can determine whether the new viruses are likely to cause human cancer. [unreadable] [unreadable] [unreadable]